AU691430B2

AU691430B2 - Intermediates useful in the preparation of 5-HT4 receptor antagonists

Info

Publication number: AU691430B2
Application number: AU60735/96A
Authority: AU
Inventors: Laramie Mary Gaster; Francis David King; Keith Raymond Mulholland; Shirley Katherine Rahman; Paul Adrian Wyman
Original assignee: SmithKline Beecham Ltd
Current assignee: SmithKline Beecham Ltd
Priority date: 1991-09-12
Filing date: 1996-07-26
Publication date: 1998-05-14
Anticipated expiration: 2012-09-09
Also published as: AU6073596A; CZ56094A3; CZ283619B6; JPH06510537A; ATE182591T1; NZ244282A; SG49153A1; WO1993005038A1; CA2118812A1; AU2541892A; NO940874L; JP3294611B2; DE69229674T2; HUT70154A; FI941178A; ES2135414T3; BR9206599A; FI941178A0; HU9400734D0; EP0604494A1

Abstract

PCT No. PCT/GB92/01649 Sec. 371 Date Jul. 28, 1994 Sec. 102(e) Date Jul. 28, 1994 PCT Filed Sep. 9, 1992 PCT Pub. No. WO93/05038 PCT Pub. Date Mar. 18, 1993 <IMAGE> (I) <IMAGE> (a) <IMAGE> (b) <IMAGE> (c) The use of a compound of formula (I) or pharmaceutically acceptable salt thereof, in which X1-(CH2)x-X2 forms a 5-7 membered ring wherein: X1 is O or S; X2 is O, S, NR or NRCO wherein R is hydrogen or C1-6alkyl; x is 1, 2 or 3; Y is O or NH; Z is sub-formula (a), (b) or (c) in the manufacture of a medicament for use in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

Description

aLJ 1, L ra~-1 e Regulation 3,2

AUSTRALIA

Patents Act 1952 COMPLETE SPECIFICATION FOR A STANDARD PATENT

(ORIGINAL)

A

*o A

A.

A

Name of Applicant: SmithKline Beecham plc Actual Inventors: Francis David KING, Mary Laramie GASTER, Keith Raymond MULHOLLAND, Shirley Katherine RAHMAN ANI Paul Adrian

WYMAN

Address for Service: DAVIES COLLISON CAVE, Patent Attorneys, 1 Little Collins Street, Melbourne, 3000.

Invention Title: "Intermediates useful in the preparation of 5-HT 4 receptor antagonists" The following statement is a full description of this invention, including the best method of performing it known to us: -1- ~pp II C I C c~s I II I -s I PI~OrI\M ICMWM 8-92.DIV 23/n7/ 1A- This application is a divisional of Application No. 25418/92, the entire contents of which is incorporated herein by reference.

This invention relates to compounds which are intermediates useful in the preparation of 5-HT 4 receptor antagonists. These antagonists are useful in the treatment of gastrointestinal disorders, CNS disorders and/or cardiovascular disorders.

European Journal of Pharmacology 146 (1988), 187-188, and Naunyn- Schniedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptarminc receptor, now dcsignated the 5-HT 4 receptor, and that ICS 205-930, which is also a 5-HT 3 receptor antagonist, antagonises at this receptor.

Some 5-HT 3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome (see EP-A-189002 (Sandoz Limited) and EP-A-201165 (Beecham Group 5-HT 3 receptor interactions which are of potential use in the treatment of IBS are those associated either with the visceral pain and abnormal perception of sensation aspects of this disease, or they are related to the ability of some 5-HT 3 receptor antagonists to cause constipation in volunteers.

ee e 20 Some 5-HT 3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [see EP-A-226266 (Glaxo Group Ltd.) and EP-A-189002 (Sandoz Limited)]. 5-HT 3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron (see Drugs of the Future 1989, 14 p.

8 7 5 F.D. King and G.J. Sanger).

PCT/GB91/00650 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT 4 receptor antagonists in the treatment of atrial arrhythmias and stroke.

EP-A-36269 (Beecham Group p.lc,) describes a group of compounds of potential use in the treatment of gastrointestinal motility disorders.

71 PAOPERUMOC54182,DIV- 12/3/% -2- WO 92/10494 (Beecham Group describes 5-HT3 receptor antagonists derived from a benzoic acid nucleus, 2,3 disubstituted by alkylenedioxy.

It has now been discovered that certain of the compounds embraced by the general formulae disclosed therein, and related compounds, have 5-HT4 receptor antagonist properties, and are therefore of potential use in the treatment of IBS or atrial arrhythmias and stroke.

The compounds described in the parent application also have a potential use in the treatment of CNS disorders such as anxiety and/or migraine, in the treatment of upper gut motility disorders and as antiemetics.

The present invention provides a compound of the formula: 15 H-Y-Z wherein Z is of sub-formula: o wherein is butyl or cyclohexylmethyl; and Y is O or NH.

These compounds are useful in the preparation of some of the compounds of formula I described in the parent application.

Specifically the compound is selected from the group consisting of 4-aminomethyl-l-butyl piperidine, 4-aminomethyl-1-cyclohexylmethylpiperidine, 1-butyl-4-pipetridinemethanol and 1-cyclohexylmethyl-4-piperidinemethanol.

lr-, I'A~l'PIMWU41192.1)IV. P1v6 The compounds of formula I or pharmaCcutically acceptable salts thereof, which may be prepared. from the compounds of the present invention include the following: Co-Y-z

R

3

R

4

(I

R,

forms a 5-7 mnembered ring wherein: X, is 0or S; is 0, S, NR or NRCO wherein R is hydrogen or alkyl; x is 1, 2 or 3; R, is hydrogen, amino, halo, alkyl, hydroxy or C, 6 alkoxy; R. is hydrogen, halo, C,_6 alkyl, C 1 6 alkoxy, nitro, amino or C 1 .6 alkylthio;

R

3 is hydrogen, halo, C,.

6 alkyl, C,.

6 alkoxy or amino; R, and R 5 are independently hydrogen or alkyl; and Y and Z are as defined above.

Examples of alkyl or alkyl containing groups include C 1

C

2

C

3

C

4

C

5

C

6

C

7

C

8

C

9 CIO, C 11 I or C 12 branched, straight chained or cyclic alkyl, as appropriate. C 1 4 alkyl groups include mnethyl, ethyl ni- and iso-propyl, iso-, sec- and tert-butyl. Cyclic alkyl includes cycl opropyl, cyclobutyl, cyclopentyl, eye] ohexyl, cycloheptyl and cyclooctyl.

V Halo includes fluoro, chloro, bromo and iodo, preferably chioro.

LL- L C VAONANNIW'q vls V2'1)1v IVIVA Suitable examples of the Xl-(CH2)x-X 2 moiety include 0-(CH2) 2 -0, 0-(CH 2 3

O-CH

2

O-(CH

2 2

-NR

4 0-(CH 2 2 -S or O-CH 2

-CONR

4 wherein any of the methylene linkages are optionally mono- or disubstituted by C 1 -6 alkyl groups, such as methyl. Preferably

X

1

-(CH

2 2 -X2 is O-(CH 2 2 -0.

R

1 is preferably hydrogen or amino.

R

2 is preferably hydrogen or halo.

R

3 is preferably hydrogen or halo.

R

4 and R 5 are often hydrogen. When R4/R 5 is C1-6 alkyl, it is often methyl. In particular R 4 and R 5 are methyl such that the disubstituent containing X 1 and X 2 is O-C(CH 3 2 -0.

A specific value of Z of particular interest is as follows: .n u (i) d glucose--phosphoric acids.

:...Examples of pharmaceutically acceptable salts include quaternary derivatives of the compounds of formula such as the compounds quaternised by compounds Rx-T wherein R is 1-6 alkyl, phenyl-C1-6 alkyl or C 5 -7 cycloalkyl, and T is a radical corresponding to an anion of an acid. Suitable examples of Rx include methyl, ethyl and n- and iso-propyl; and benzyl and phenethyl. Suitable examples ofT include halide such as chloride, bromide and.iodide.

-a a Ip ~L I R avi!Iv. I V1194llV LHI~ The compounds of formula whcrein CO-Y is an ester or amide linkage are prepared by conventional coupling of the Z moiety with the appropriate acid. Suitable methods are as described in GB 2125398A (Sandoz Limited), GB 1593146A, EP-A-36269, EP-A-289170 and WO 92/05174 (Beecham Group When CO-Y is replaced by a heterocyclic bioisostere, suitable methods are described in EP-A-328200 (Mcrck Sharp Dohme Limited).

The invention also comprises a process for preparing the novel compounds of formula (I) which comprises reacting an appropriate benzoic acid derivative with an appropriate alcohol or amine. A process comprises reacting a benzoic acid derivative Nwherein the aromiatic substitucnts are as required in the end compound of formula or substituents convertible thereto, with an alcohol or amine according to the present invention or a group convertible thereto, and thereafter if necessary, converting the benzoic acid substituents and/or Z, and optionally forming a pharmaceutically acceptable salt.

Suitable examples of conversions in the aromatic substituents include ~chlorination of hydrogen to chloro, reduction of nitro to amino, dehydrohalogenation such as debromination, and/or elaboration of a 2,3- 20 disubstituted benzoic acid with ethylene glycol to form the benzodioxan.

Suitable examples of conversions in the Z containing moiety include conventional modifications of the N-substituent by substitution and/or deprotection.

Any elaboration ofX and/or Z is, however, usually carried out prior to ester or amide coupling.

S. a S* The compounds of formula prepared from the novel intermediates of the present invention are 5-WJ-T receptor antagonists and it is thus believed may generally be used in I-r I I I I K. 11iinU~i D~IV- w -0the treatment or prophylaxis of gastrointestinal disorders, cardiovascular disorders and CNS disorders.

They are of potential interest in the treatment of irritable bowel syndrome (IBS), in particular the diarrhoea aspects of IBS, these compounds block the ability of 5-HT to stimulate gut motility via activation of enteric neurones. In animal models of IBS, this can be conveniently measured as a reduction of the rate of defaecation. They are also of potential use in the treatment of urinary incontinence which is often associated with IBS.

They may also be of potential use in other gastrointestinal disorders, such as those associated with upper gut motility, and as antiemetics. In particular, they are of potential use in the treatment of the nausea and gastric symptoms of gastro-oesophageal reflux disease and dyspepsia.

Antiemetic activity is determined in known animal models of cytotoxicagent/radiation induced emesis.

Specific cardiac 5-HT 4 receptor antagonists which prevent atrial fibrillation and other atrial arrhythmias associated with 5-HT, would also be expected to reduce occurrence of stroke (see A.J. Kaumann 1990, Naumyn-Schmiedeberg's Arch. Pharmacol. 342, 619-622, for appropriate Sanimal test method).

*Anxiolytic activity is likely to be effected via the hippocampus (Dumuis et al 1988, Mol Pharmacol., 34, 880-887). Activity can be demonstrated in standard animal models, the social interaction test and the X-maze test.

Migraine sufferers often undergo situations of anxiety and emotional stress that precede *he appearance of headache (Sachs, 1985, Migraine, Pan Books, London). It has also been observed that during and within 48 hours of a migraine attack, cyclic AMP levels are considerably increased in the cerebrospinal fluid (Welch et al., 1976, Headache 16, 160-167). It is believed that a migraine, including the prodomal phase and the associated increased levels of cyclic AMP are related to stimulation of 5-HT 4 receptors, and hence that administration of a 5-HT 4 antagonist is of potential benefit in relieving a migrainc attack.

I -J ':;.ol'liMi wCllnY nIV 180v9r, -7- The invention also provides a pharmaceutical composition comprising a compound of formula or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Such compositions are prepared by admixture and are usually adapted for enteral such as oral, nasal or rectal, or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, nasal sprays, suppositories, injectable and infusable solutions or suspensions. Orally administrable compositions are preferred, since they are more convenient for general use.

Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents. The tablets may be coated according to well known methods in the art, for example with an enteric coating.

Suitable fillers for use include cellulose, mannitol, lactose and other similar agents. Suitable disintegrants include starch, polyvinylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, magnesium stearate.

20 Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elxirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxyrnethylcellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or I L _I~CII ~a31 O 1 li |l \M )l ,2 I V IW 1 «6 -8propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.

Oral liquid preparations are usually in the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs or are presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), preservatives, and flavouring or colouring agents.

The oral compositions may be prepared by conventional methods of blending, filling or tabletting. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.

For parenteral administration, fluid unit dose forms are prepared containing a compound of the present invention and a sterile vehicle. The compound, depending on the vehicle and the concentration, can be either suspended or dissolved. Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants .20 such as a local anaesthetic, preservatives and buffering agents are also S..dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.

Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure of ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.

s I I IC-~ L s a c~ I':\OI'ER\II(2iM)it.91IV- IRV/I/6m -9- The parent invention further provides a method of treatment or prophylaxis of irritable bowel syndrome, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine in mammals, such as humans, which comprises the administration of an effective amount of a compound of the formula or a pharmaceutically acceptable salt thereof.

An amount effective to treat the disorders hereinbefore described depends on the relative efficacies of the compounds of the invention, the nature and sever.ny of the disorder being treated and the weight of the mammal.

However, a unit dose for a 70kg adult will normally contain 0.05 to 1000mg for example 0.5 to 500mg, of the compound of the invention. Unit doses may be administered once or more than once a day, for example, 2, 3 or 4 times a day, more usually 1 to 3 times a day, that is in the range of approximately 0.0001 to 50mg/kg/day, more usually 0.0002 to mg/kg/day.

No adverse toxicological effects are indicated within the aforementioned dosage ranges.

The parent invention also provides a compound of formula or a pharmaceutically acceptable salt thereof for use as an active therapeutic substance, in particular for use in the treatment of irritable bowel syndrome, gastro-oesophageal reflux disease, dyspepsia, atrial arrhythmias and stroke, anxiety and/or migraine.

The following Examples illustrate the preparation of compounds of formula as described in the parent application; the following descriptions relate to intermediates (Descriptions 1-3 and 11 are nuclei incorporating intermediates containing Xi-(CH 2 2 Descriptions 4-9 and 10 are side chain Z containing intermediates and Descriptions 12 onwards are piperidyl intermediates prepared from the corresponding compound wherein Z is sub-formula

NR

aNRa II/X a1el I g ill I prepared from the corresponding pyridyl derivative. Descriptions 4 to 7 correspond to intermediates according to the present invention.) Examples Rl 1L2 R 3 XlIX 2 y 0, 0* 00**

S

04 0 0 0**t 0* 00 0 00 0*t* *0 o *0 El NH 2 E2 NH 2 E3 H E4 H

H

E6 NH 2 E7 NH 2 E8 NH 2 E9 NH 2 E10 NH 2 Ell H E12 NH 2

O-(CH

2 2

-O

O-(CH

2 2

-O

O-(CH

2 2

-O

O-(CH

2 )2-O

O-(CH

2 )2-O

O-(CH

2 2

-O

O-(CH

2 2

-O

O-(CH

2 2

-O

O-(CH

2 2

-O

O-(CH

2 2

-O

O-(CH

2 2

-O

O.(CH

2 2

-O

Wi Wi Wi Wi Wi Wi (ii) Mv ax Mv eq (ii) (vi) eq (vi) eq p.\OppK"MCuZ4 j&S'2IV- 19MY/6 -1I1I- Examples (continued)

R

1

R

2

R

3

X

1

/X

2 Y Z E13 E14 E16

NH

2

NI{

2

NH

2

NE

2 E17 H E18 H E19 H

H

E21 H

O-(CH

2 )2-O NH epm

O-(CH

2 2 -O NH Wi

O-(CH

2 2 -O NH (ii)

O-(CH

2 2 -O 0 Pm 0-(CH 2 )2-0 ox pp 0-CH 2 -0 0 Wi 0-CH 2 CONH 0 Wi 0-CH 2

CONCH

3 0 Wi

O-(CH

2 2 N'H 0 Wi by 1 ,2,4-oxadiazole (ii) (iv) /Nv/IW Bu (vi) Good 01.

at epm I -ethyl-4-piperidyl pm =4-piperidylmethyl ox =where CO-Y replaced pp =3 iperidino)propyl (iii) I

N

(v PA0OIlL\iC254l$.flDIV. ig96 12- Examples (continued)

X

1

/X

2

O-(CH

2 2

Y=O

R

1

R

2

R

3 E22 E23 E24 E26 E27 E28 E29 20 E31 E32 E33 E34

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2

NH

2 1-methyl-4-pipez-idylmethyl 1-e thyl-4- pip eridylmnethyl 1-propyl-4-piperidylmethyl 1-ibutyl-4-piperidylmethyl 1-cyclopropylmethyl-4-piper-idylinethyI 1-pentyl-4-piperi dylmethyl 2-methylbutyl-4-piperidylme thyl 2-methoxyethyl-4-piperidyl methyl 1-benzyl-4-piperidylmethyl 2-cyclohexylethyl-4-piperidylmethyI 1-hexyl-4-piperi dylmethyl 1-heptyl-4-piperi dylniethyl 1-octyl-4-piperidylmethyl *000 0000 0* 0 0 0000 E35 NH2 E N 2 C1 H 1-nonyl-4-piperidylmethyl P.10TRW02.4)8-2,DV -IRfV96 13 Examples (continued) [XI/X9) O-(CH 2 2 Y=1

R

3

Z

0 0.

0000 0* 0 E36 E37 E38 E39 E41 15E42 E43 20 E44 E45 E46 E47 E48 E49

RI

NH

2

NH

2 NH2

NH,)

NH

2 1'H2

NH

2

NH

2

NH

2

N'H

2

NH

2 N119 R2 Cl Cl

C'

C1 Cl C1 Cl C1 Cl Cl Cl

CI

Cl Cl

H

[Xi/k2

H

1-decyl-4-piperidylmethyl 1-undecyl-4-piperidylmethyl 1-dodecyl-4-piperidylmethyl 1-(4-fluorobenzyl )-4-piperidylme thyl 1-(4-methoxybenzyl)-4-piperidylmethyl 1-(4-methylbenzyl )4-piperidylmethyl 1-phenylethyl-4-piperidylmethyl

~=O-(CH

2 2

Y=NH]

1-pentyl-4-piperidylmethyl I -cyclohexylethyl-4-piperidylrnethyl 1-isobutyl-4-piperidylmethyl 1-(2-methylbutyl)-4-piperidylmethyl 4-pipezidylinethyl 1-methyl-4-piperidylmethyl l-propyl -4-piper-idylmethyl 1-benzyl-4-piperidvlrnethyl wnm E51 E52 E53 E54 R1 2

NH

2 Cl

H

Cl

I

H

Br 14 Examples (continued) [Xl/Xg O-(CH9)c,-O; Y=0]

R

3 Z H 1-butyb-l-methyl-4-piperirlylmethyI iodide H 1-butyl-4-pipeiidylmethyl H l-butyl-4-piperidylmethyl Br 1-butvl-4-piperidylmethyl ft. ft.

ft ft ft

MEN

I':\OPliBR\MU C 2418-2DIV 18/96 Example 1 8-Amino-7-chloro-(-1butyl-4-piperidyl)methyl- 1,4-benzodioxan-5carboxylate (El) A suspension of 8-amiIo-7-chloro-1,4-benzodioxan-5-carboxylic acid (prepared from the corresponding 7-H acid 1 by chlorination of the protected form) (720 mg) was dissolved in acetonitrile (10 ml). Bis carbonyldiimidazole (500 mg) was added and the reaction mixture stirred for 2 hours. The solvent was removed in vacuo and the residue dried. A solution of 1-butyl-4-piperidinemethanol (510 mg) in dry THF (20 ml) was added dropwise to a solution of nbutyllithium (1.88 ml of a 1.6M solution in hexane) at 000C and the solution was stirred for 15 minutes. The imidazolide from above was redissolved in dry THF (25 ml) and the solution added dropwise to the solution of the lithium alkoxide in dry THF. The reaction mixture was stirred at room temperature overnight.

After removal of solvent the residue was partitioned between EtOAc and

H

2 0 and the EtOAc layer separated. This solution was washed several times with water and dried (MgS04). Evaporation of solvent gave a yellow gum that was purified by column chromatography on SiO 2 using CHC13, 95%, MeOH, 5% as eluant. The product was isolated as the hydrochloride salt, mp 243-4oC.

1 H NMR 250MHz (CDC1 3 (free base) 5: 7.49 4.48 (bs,2H), 4.26-4.38 4.08 2.93-3.05 (bd,2H), 2.30-2.40 1.20-2.05 (m,11H), 0.90 (t,3H).

Examples 2 to 12 The following compounds were prepared analogously: 8-Amino-(l-butyl-4-piperidyl)methyl-1,4-benzodioxan-5carboxylate (E2) 1 H NMR 250MHz (CDC13) (free base) I I L~L~ i;\O1f3RMJCV512,9DIV jg/7M6 -16- 7.39(d,1H) 6.24(d,1K) 4,3-4.42(m,4H) 4.05-4.16(4H) 2.9-3.1(bd,21I)2.3- 2.4(in, 2H) 1.2-2.05(m, 1111) O.90(t,3H) 7-Bromo-5-(-butyl-4-piperidyl)methyl-1,4-benzodioxal-5carboxylate (E3) mp 205-6 0 C (hydrochloride salt) 1 0 1 H NMR 25OMIHz (CDCl 3 (free base) 7.5(d,1H)7.12(d,1H), 4.3-4.42(m,4H) 4.12(d,2H) 2.9-3.05(bd,2H) 2.3- 2.4(mn, 2H) 1.22-2.05(m,11H) 0.92(t,3H) (1-Bu tyl-4-piperi dyl)ne thy 1- 1,4- benzodioxan- 5-carboxylate (E4) mp 144-60C (hydrochloride salt) 1 H NMR 250MHz (CDCl 3 )(free base) 6: 7.38(dd,1K) 7.0(dd,1K) 6.82(t,1H) 4.28-4.4(m,4H) 4.12(d,2H) 2.9- 3.05(bd,2H) 2.3-2.4(rn,2H) 1.22-2.05(m,11K) 0.92(t,3H) Chloro- (1-bu tyl-4-pipe ridy1) m ethyl1- 1, 4-be nzo di oxa carboxylate mp 185-60C (hydrochloride salt) 1 H NMR 250 MiHz (CDC1 3 (free base) 7.37(d,1H), 7.02(d,1H),4.25-4.40(m,4K), 4. 14(d,2H), 2.98(bd,2H), 2.28- 2.38(m,2H), 1.24-2.00(m,11H), 0.92(t,3H) 8-Amino-6,7-dicbloro- (-butyl-4-piperidyl)me thyl- 1,4-benzodioxan- 5-carboxylate (E6) mp 168-90C (hydrochloride salt) J,:%OPE*K\Mj".qIR,9LDjv. IWV96 -17 1 H NMR 250 MHz (CD C1 3 (free base) 6: 4.39(s,2H), 4.28-4.37(m,4H), 4.15(d,2H-), 2.9-3.05(bd,2H), 2.3-2.4(m,2H), 1.22- 1.98(m, 11H),0.92(t,3H) 8-Amino-7-io do- (l-cyclohexylm ethyl -4 -pi peri dyl) me thyl- 1, 4- (E7) 1H NMR 250 MIHz (CDCl 3 (free base) 7.79(s, 1H), 4.50-4.59(d,2H), 4.28-4.37(in,4H), 4.15(d,21{), 2.90-3.06 (bd,2H), 0..80-2.30(m,20H) 8-Amino-7-chloro- 1,4-benzodlioxan- (ax-3-quinolizidiriyl)methyI carboxylate (E8) nip 139-40 0

C

1 H NMR 250 MHz (CDCI 3 (free base) 6: 7.42 4.19-4.5 (m,8H) 2.72(dd,lH), 2.60(bd,lH), 1.10-2.11(m,14H) 8-Amino-7-chloro- 1,4-benzodioxan- (eq- 3-quinolizi dirxyl)methyl carboxylate (E9) 1 H NMR 250MHz (CDC1 3 (free base) 8: 7.49(s,1H), 4.48(bs,2H), 4.28-4.38(m,4H),3.95-4. 15(m,2H), 3.0(bd, 1H), 2.83(bd,1H), 1.01-2.20(m,14H) 8-Amino-7-chloro- (l-cyclohexylmethyl-4-piperidyl) methyl- 1,4- (ElO) nip 185-60C (hydrochloride salt) 1H NMR 250MHz (CDC1 3 (free base) P:\OUTUk\NIMiC25IX.92.I imm 3 18- 6: 7.49(s,lH), 4.48(bs,2H), 4.30-4.38(m,4H),4.08(d,2H), 2.82-2.91(bd,2H), 2.10(d,214), 0.80-1.95(m,18H) eq-Quinolizidin-2-yhnethyl-7-chloro- 1,4-benzodioxan-5carboxylate (Ell) rnp 191-192 0 C (hydrocloride salt) 1 H NMIR (d 6 DMSO) (MCI salt) 6: 7.24(d,1H), 7.20(d,1H), 4.28-4.36(m,4H), 4.11(d,2H), 3.25-3.36(m,2H), 2.76-3. 11(m, 1H), 2.0 1-2. 13(m, 1H), 1.36- 1.92(n, eq-Quinolizidiri-2.ylme thyl- 8- amino- 7-chioro- 1, 4-be nzo, dioxan- carboxylate (E12) nip 173-1750C 1H NMR 250 MHz (CDCI 3 (free base) 6; 7.48(s,1H), 4.45(brs,2H), 4.28-4.40(m,4H), 4.07(d,2H), 2.76-2.94(m,2H), 1.00-2. 15(m, 14H) Example 13 8-Amino-7-chloro- (l-ethyl-4-pi peridyl )ne thyl- 1,4-benzodioxan-5carboxamide (E13) A solution of 8-amino-7-chloro-1,4-benzodioxan-5-carboxylic acid (see V Example 1) (500mg, 0.OO22mole) in acetonitrile (3Ornl) was treated with biscarbonyl diirnidazole (356mg, 0.0022 mole). The mixture was stirred at room temperature for 2 hours.

35 A solution of 1-ethyl-4-aminomethylpiperidine (312mg, 0.0022 mole) in acetonitrile (25 ml) was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between EtOAc and H20O. The EtOAc layer was I 8.02,01V IVIOM -19removed, washed several times with Honl. dried (MgSO 4 and concentrated to give an orange gum that was purified by column chromatography on SiO 2 using chloroform with increasing proportions of methanol as eluant. The product was isolated as a pale gum.

1 H NMR 250MHz (CDCI 3 (free base) 7.69(s,1H), 7.50(bt,1H), 4.29-4.39(m, 6H), 3.25(t,2H), 2.94(bd,2H), 2.38(dd,2H) 1.20-1.95(m,7H), 1.01(t,3H) Examples 14 arnd The following compounds were prepared by the method described for Example 13.

8-Amino-7-chloro-(1-butyl-4..piperidyl)methyl- 1,4-benzodioxan-5carboxaxnide (E14) mp 75-60C 1 H NMR 250MHz (CDCI 3 (free base) 6: 7.73(s,1H), 7.58(bt,1H), 4.30-4.45(m,6H), 3.3(t,2H), .02-3.1(bd,2H), 2.39.(m,2H), .18(,H,09(,H 20 Example 16 8-Amino-7-chloro-(4-piperidylmethyl)- 1,4-benzodioxan-5carboxylate hydrochloride (E16) a) To a stirred solution of 8-amino-7-chloro-1,4-benzodiox-an-5carboxylic acid 1 (1.10g) in acetonitrile was added bis-carbonyldiimidazole (0.77g). The reaction mixture was stirred at room temperature for hours. The solvent was removed under reduced pressure to afford crude 8-amino-7-chjoro- 1,4-benzodioxan-5-imjdazolide.

b) To a solution of N-tert-butoxycarbonyl-4-hydroxymethyl piperi dine (0.25g) in dry TIHF (l0mi) was added methyllithium (1.5M in diethylether; 0.78m1) at 000 under a nitrogen atmosphere. Stirring was continued at ambient temperature for 10 min. 8-Amino-7-chloro- 1,4-benzodioxan-5ixnidazolide (0.33g) in TH-F (10mi) was added to the reaction mixture and stirring continued for 2 hours. The reaction mixture was cooled to 0OC and water was added. The solvent was removed under reduced pressure and the residue partitioned between chloroform and water. The organic phase was washed with water dried (Na 2

SO

4 filtered and concentrated in uacuo. Flash chromatography on silica using chloroform ~*:and ethanol as eluant gave the title compound (0.26g).

1 H NMR 250MHz (CDCI 3 7.47(s,1H), 4.49(s,2H), 4.08-4.22(m,4H), 2.64-2.80(m,2H), 1.84- C) HOl(g) was bubbled into a cooled solution of 8-amino-7-chloro-(Nte rt-butoxycarb onyl-4- pipe ri dylmethyl)- 1, 4-benzodioxan- 5- carboxylate (0.26g) in dioxan (50m1) for 25 min. The solvent was concentrated in vacuo and the residue triturated with Et9)O to afford pure title compound (0.12g).

mp 249-2510C 1H NIAR 250MHz (DMSO) -21 6: 8.99-9. 10(m,1H), 8.59-8.78(m,1H), 7.29(s,1H), 5.73(s,2H), 4.25- 4.34(s,4H), 4.03(d,2H-), 3.20-3.42(m,2H), 2.75-2.97(m,2H), 1.76- 2.06(zn,3H), 1.48-1.57(m,2H) Example 17 5[3- (Piperidino )propyl]-3- [benzo- 1,4.-dioxan-5-yl3- 1,2,4-oxadiazole (E17) 1,4-Benzodioxan-5-carboxarnide oxime (D3) (0.300g 1.55 mmol) was dissolved in dry TH{F (l0mi) with stirring, and treated with ground 4A molecular sieves under nitrogen. After 30 minutes, sodium hydride dispersion in mineral oil) (0.051ig, 1.71 rnrol) was added. The mixture was then heated to reflux. After 30 minutes, the mixture was allowed to cool for a short period and ethyl-4-(piperidino) buty-rate (0.340g, 1.71 inmol) was added. The reaction mixture was then heated to reflux for a further 2.5h, before being allowed to cool. The reaction mixture was then filtered. The filter pad was then washed with TEF The filtrate o 20 was evaporated under reduced pressure. The residue was purified by silica-gel chromatography, eluting with pentane: EtOAc 1:1->2:3 to give the title compound as a pale yellow oil, which was converted to the hydrochloride salt mp 175-1760C.

IH NMR 25OM~z (CDCI 3 12.20-12.5(s br, 1H), 7.52(dd, 6.90-7.08 (m,2F1), 4.45(m,2H), V 4.35(m,2H), 2.97-3.20(m,4H), 2.47-2.80(rn,4H), 2.15- 2.45(m,2H), 1.74-2.00(rn,3H), 1.30-1.54(m, 1H) 22 Example 18 (1-Butyl-4-piperidyl)methyl- 1,3-benzoclioxole-4-carboxylate hydtrochlor-ide (E18) Following the procedure outlined in Example 1 1,3-benzod-ioxole-4carboxylic acid (Dl1) (705 mng) was converted to the title compound (393 mig, 29%) mp 168-90C.

1 H NMR 250 MiHz (CDCI 3 7.4 1H), 6.98 1K), 6.86 1H), 6.10 2H), 4.20 2H), 3.04 (br d, 2H), 2.45-2.3 (mn, 2H), 2.1-1.2 (in, 11K), 0.94 3H).

Examples 19 to 21 The parent acids for Examples 19-2 1 are described in EP-A-407 137 and 313393 (Yoshitomni).

(1-Butyl-4-piperidyl)methyl-6-chloro-3,4-dihydro-3-oxo-2H- 1,4benzoxazine-8-carboxylate (E19) nip 245-2470'C (KCI salt) 1 K NMR 250 M~z, (CD 3 SO CD 3 (KCI salt) 8: 11.17 1K), 10.34-10.10 1K), 7.41 1K), 7.21 1K), 4.80 2H), 4.22 2K), 3.57 (mn, 2H), 3.20-2.85 (mn, 4K), 2. 12-1.95 (mn, 3K), 1.90-1.60 (mn, 4K), 1.40 (mn, 2K), 1.00 3K) (1-Butyl-4-piperidyl)methyl-6-chloro-4-methyl-3,4-dihydro-3-oxo- 2H- 1,4-benzoxazine- 8-carboxyla te nip 87-880C 1 K NAIR 250 MHz, (CDCI 3 1XflJ96 23 7.49 1H), 7.10 1H), 4.18 2H), 3.38 3H), 3.00 2H), 2.33 (t, 2H), 1.97 2H), 1.78 (mn, 3H), 1.54-1.25 (in, 6H), 0.92 3H) (1-Butyl-4-piperidyl)methyl.6-chloro-3,4-dihydro-2H- 1,4benzoxazine-8-carboxylate (E21) nip 177-1780C (KCl salt) 1 H NMR 250 MI~z, (CD 3 SO CD 3 (KCl salt) 10.28 1H), 6.85 (in, 2H), 6.58 1H), 4.23 2K), 4.15 1K), 3.67 2H), 3.45 (in, 3K), 3.10-2.90 (in, 3H), 2.15-1.92 (mn, 3K), 1.88-1.60 (mn, 4H), 1.40 (in, 2H), 1.00 3H) Example 22 8-Amino-7-chloro-5-(l-methyl-4-piperi dinylmethyl)- 1,4- 20 benzodioxan carboxylate hydrochloride (E22) To a solution of 8-axnino-7-chloro-5-(1K-4-piperidylmethyl)-1,4berizodioxan carboxylate (E15) (100mg) and triethylainine (70p.i) in acetone (i5mi) was added iodoniethane (200a). The reaction mixture was 25 stirred at ambient temperature for 64h. The solvent was concentrated under reduced pressure and the residue partitioned between chloroform and water. The organic phase was dried (Na2SO 4 filtered and concentrated in uacuo. Chromatography on silica using chloroform and ethanol as the eluant gave pure product. Treatment with ethereal KOI afforded the title compouind 1 H NMR 250 MHz (CDCI 3 (free base) 6: 7.49 1H), 4.53 (bs, 2H), 4.3 1-4.44 (mn, 4K), 4.19 2H), 3.49 2H), 2.69-2.85 (in, 5H), 1.97-2.15 (in, PAOMMIJ023418-92JAV I RnI96 24 Examples 23 to 43 Following the procedure outlined in Example 22, from the compound of Example 16, the following compounds were obtained: 8-Amino- 7-chloro-5- (1-e thyl1-4-piperi dyl)m e thyl- 1,4-benrzodioxan carboxylate, hydrochloride (E23) 1 H NMR 250MFz (CDCl 3 (free base) 7.47 1H), 4.53 (bs, 2H), 4.29-4.46 (mn, 4H), 4.17 2H), 3.44 2H), 2.95 2H), 2.51-2.69 (in, 2H), 1.90-2.12 (mn, 5H), 1.40 3H) 8-Amino-7-chloro-5(l-propyl-4-pi pen dyl)ne thyl- 1,4-benzodioxan carboxylate hydrochloride (E24) 1 H NMR 250 MHz (CD 3

OD)

7.44 1H), 4.27-4.38 (in, 4H), 4.16 2K), 3.64 2H), 2.94-3.13 (mn, 4H), 2.03-2.17 (mn, 3K), 1.59-1.88 (in, 4K), 1.03 3H) 8-Amino-7-chloro-5-(l-isobutyl-4-piperi dyl )methyl- 1,4-benzodioxan ****carboxylate hydrochloride 1 H NMR 250MHz (CDCl 3 (free base) 68: 7.50 1H), 4.48 (bs, 2K), 4.31-4.39 (mn, 4H), 4.09 2K), 2.89 2K), 2.08 2H), 1.69-1.95 (in, 6K), 1.3 1-1.49 (in, 2K), 0.91 6H) 8-Amino-7-chloro-5i> (l-cyclo pro pylme thyl-4- pi peridyl) me thyl-l,4benzodioxan carboxylate hydrochloride (E26) 1 H NMR 250MHz (CDCl 3 (free base) 6: 7.49 1H), 4.52 (bs, 2K), 4.29-4.45 (mn, 4K), 4.14 2H), 3.39 2K), 2.58 2K), 2.29-2.48 (in, 2K), 1.69-2.00 (mn, 5H), 1.04-1.18 (in, 1H), 0.54 2K), 0.27 2K) I I_~ L~Oll~~ \1M 2DnV I 8rtI!6 8-Amino-7-chloro-5-(1-pentyl-4-piperidinyl)ie thyl- 1,4-benzodioxaf carboxylate hydrochloride (E27) 1H NMR 250MHz (CD 3

OD)

7.43 1H), 4.31-4.41 4H), 4.17 2H), 3.65 2H), 2.95-3.17 (m, 4H), 2.01-2.18 3H), 1.61-1.86 4H), 1.29-1.49 4H), 0.95 3K) 8-Amiino-7-chloro-5-(2-methylbutyl-4-piperidyl)ethyl- 1,4benzodioxan carboxylate hydrochloride (E28) 1H NMR 250MHz (CD 3

OD)

7.43 1H), 4.28-4.43 4H), 4.18 2H), 3.65 2H), 2.95-3.19 (in, 4H), 2.02-2.19 3H), 1.59-1.78 5H), 0.97 6H) 8-Amino-7-chloro-5-(2-methoxye thyl4-piperidylh ethyl- 1,4benzodioxan carboxylate hydrochloride (E29) 1 H NMR 250MHz (CDC1 3 (free base) 7.49 1K), 4.49 (bs, 2K), 4.30-4.42 4H), 4.11 2K), 3.52 2H), 3.35 3H), 3.01 2H), 2.60 2H), 2.03 2H), 1.73-1.84 3K), 1.38- 1.57 2H) 8-Ainino-7-chloro-5-(1-benzyl-4-piperidyl)methyl- ,4-benzodioxan carboxylate hydrochloride 1 H NMR 25OMHz (CDC1 3 (free base) 7.49 1K), 7.22-7.40 5K), 4.49 (bs, 2K), 4.28-4.52 4H), 4.10 (d, 2H), 3.50 2H), 2.94 2K), 2.00 2K), 1.70-1.85 3K), 1.33-1.51 2H) 8-Aino-7-chloro-5- (2-cyclohexylethyl-4-piperi dinyl)methyl-1,4benzodioxan carboxylate hydrochloride (E31) 1H NIMR 250 MHz (CDCI 3 (free base)

I~_

i8nm -26- 6: 7.49 1H), 4.47 (bs, 2H), 4.29-4.41 (in, 4H), 4.10 2H), 3.01 2H1), 2.33-2.44 (mn, 2H1), 1.99 2H1), 1.35-1.87 (mn, 121H), 1. 10-1.31 (mn, 4H), 0.83- 1.01 (mn, 2H1) 8-Amino-7-chloro-5-(1-hexyl-4-piperidyl)xnethyl- 1,4-benzodioxa~n carboxylate hydrochloride (E32) 1H1 NMR 250 MHz (CDCI 3 (free base) 6: 7.47(s, 1H), 4.48(bs,2H), 4.32-4.42(in,411), 4.15(d,2H), 3.09-3.24(in,2H), 2.46-2.59(in,2H), 2.09-2.28(m,2H), 1.79-1.91(m,3H), 1.55-1.73(in,4H), 1.25- 1.37(in,6H), 0.84-0.92(in,3H) 8-Amino-7-chloro-5- (1-heptyl-4-piperidyl)mnethyl 1,4-benzodioxan carboxylate hydrochloride (E33) 1H1 NMR 250 MiHz (CDC1 3 (free base) 6: 7.48(s,1H), 4.46(bs,2H), 4.30-4.39(rn,4H), 4.12(d,.2H), 3.11(d,2H), 2.47(t,2H), 2.04(t,211), 1.79-1.90(m,3H), 1.52-1.69(in,4H), 1.29-1.45(m,8H), 0.83-0.9 1(m,3H) 8-Ami no- 7-c hloro- 5- (1-o ctyl-4- p iperi dy1) m ethylI- 1,4-be nzo di oxa n carboxylate hydrochloride (E34) 1H NMR 250 MHz (CDCI 3 (free base) 8: 7.50(s, 11), 4.46(m,2H), 4.3 1-4.39(m,4H), 4. 12(d, 2H), 3.04-3. 13(in,2H), 2.38-2.48(m,2H), 2.01-2.16(m,2H), 1.77-1.88(rn,3H), 1.51-1.65(m,4H), 1.24- 1.32(rn,1OH), 0.85-0.91(in,3H) 8-Amino-7-chloro-5 .(-nonyl-4-piperidyl)methyl- 1,4-benzodioxan carboxylate hydrochloride 1H1 NMR 250 MHz (CDCI 3 (free base) wm 27 0.93(m,3H) carboxylate hydrochloride (E36) 1H NMR 250 MHz (CDC1 3 (free base) 7.41(s,1H), 4,44(bs,2H), 4.24-4.32(m,4H), 4.O8(d,2H), 3.15(d,21{), 2.48- 2.57(zn,2H), 2.24(d,2H), 1.57-1.88(in,7H), 1.13-L.28(m,14H), 0.79- 0.84(rn,3H) 8-Amino-7-chloro-5-( 1-undecyl-4-piperidyl)xnethyl 1-4-benzodioxan carboxylate, hydrochloride (E37) 1 H NMR 250 MHz (CDC1 3 (free base) 8: 7.49(s,1H), 4.50(bs, 2H), 4.32-4.41(m,4H), 4.15(d,2H), 3.19(d,2H), 2.50- 2.58(na,2H), 2.17-2.29(rn,2H), 1.80- 1.92(m,3H), 1,60- 1.78(rn,4H), 1.21- 1.35(m,16H), 0.88-0.92(ni,3H) 8-Amino-7-chloro- 5- do decyl-4-pi peri dyi)me thyl- 1, 4-benzo dioxan carboxylate, hydrochloride (E38) 1H. NMR 250 MHz (CDC1 3 (free base) 6: 7.49(s,1H), 4.49(bs 1 2H), 4.33-4.4 1(m,4H), 4.14(d,2H), 3.18(d,2H), 2.49- 2.57(m,3H), 2.22(t,2H), 1.80-1.94(m,3H), 1.57- 1.76(m,4H), 1.22- 1.33(m,18H), 0.85-0.91(m,3H) a 8-Amino-7-cbloro-5-( 1-(4-fluorobenzyl)-4-piperi dyl) methyl- 1,4- ::.benzodioxan carboxylate hydrochloride (E39) 1 H NMR 250 MHz (CDC1 3 (free base) 6: 7.48(s,1H), 7.27-7.38(m,2H), 7.01(t,2H), 4.49(bs,2H), 4.30-4.39(m,4H), 4. 11(d,2H), 3.53(s,2H), 2.94(d,2H), 2.04(t,2H), 1.72- 1.84(m,3H), 1.39- 1.52(m,2H) m PAOI-EKINUM$418-91 DIV W7,96 28 8-Ainino-7-chloro-5- 1-(4-methoxy ,benzyl)-4-piperidyl)me thyl- 1,4benzodioxan carboxylate hydrochloride 1H NMR 250 MHz (CDCl 3 (free base) 7.48(s,1H), 7.22(d,2H), 6.85(d,2H), 4.49(bs,2H), 4.29-4.36(rn,4H), 4.09(d,2H), 3.78(s,3H), 3.47(s,2H), 2.91(d,2H), 1.96(t,2H), 1.70- 1.80(m,3H), 1.29-1.47 (m,2H) 8-Amino-7-c hlo ro-5- thylbenzyl)-4- p iperi dyl) me thy 1- 1,4benzodioxan carboxylate hydrochloride (E41) 1 H NMR 250 MHz (CDCl 3 (free base) 155: 7.48(s,1H), 7.22(d,2H), 7.12(d,2H), 4.45(bs,2H), 4.30-4.38(m,4H), 4.10(d,2H), 3.47(s,2H), 2.92(d,2H), 2.33(s,3H), 2.00(t,2H), 1.70- 1.81(m,3H), 1.32-1.50(m,2H).

8-Amino-7-cbloro-5-(l-phenethyl-4-piperidyl)methyl-1,4- ~.benzodioxan carboxylate hydrochloride (E42) 1 H NMR 250 MHz (CDC1 3 (free base) 8: 7.50(s,1H), 7.15-7.34(m,5H), 4.49(bs,2H), 4.28-4.41(m,4H), 4.13(d,2H), 3.07(d,2H), 2.79-2.89(m,2H), 2.55-2.65(m,2H), 2.07(t,2H), 1.71-1.90(m,3H), 1.38- 1.54(m,2H) Example 43 8-Ainino-7-chloro- 1,4-benzodioxan-5- -pentyl-4-piperidyl)methyl carboxamide hydrochloride (E43) A solution of 8-acetamnido-7-chlorobenzodioxan-5-(1-pentyl-4piperidylmethylcarboxamide (DIM) (60mg) in ethanol (l0mi) was treated with 10% aqueous NaOH solution (1l10 il). The resultant mixture was heated to reflux for 5h. The solvent was removed in vacuo and the residue PIK\RNISCk254I8-92.DIV =19lJ6 29 partitioned between water and chloroform. The organic phase was dried (Na 2

SO

4 filtered and concentrated in uacuo to afford an oil. Treatment with ethereal HCI gave pure title compound (39mg).

1H- NYR 250 MHz (CDCI 3 (free base) 7.70(s,1H), 7.42-7.53(m,1H), 4.24-4.49(m,6H), 3.27(t,2H), 2.88(d,2H), Examples 44-46 Following the procedure outlined in Example 43 the following compounds were obtained: 8-Amino-7-cbloro- 1,4-benzodioxan-5- -cyclohexylethyl-4piperidinyl)methyl carboxamide hydrochloride (E44) 1 H NMR 250 MHz (CDCl 3 (free base) V.06, 5: 7.69 1H), 7.42-7.53(mn,1H), 4.22-4.38(m,6H), 3.24(t,2H), 2.85(d,2H-), 2.18-2.31(rn,2H), 1.81(t,2H), 0.95-1.72(m,16H), 0.70-0.93(m,2H) 8-Amino-7-chloro-1,4-benzodioxan-5-( 1-isobutyl-4-piperidyl)methyl carboxamide hydrochloride 1 H NMR 250 MHz (CDCI 3 (free base) 0 6: 7.78(s,1H), 7.49-7.59(m,1H), 4.32-4.45(m,6H), 3.34(t,2H), 2.88(d,2H), 6 30 2.07(d,2H), 1.52-1.91(m,6H), 1.23-1.40(m,2H), 0.89(d,6H).

8-Amino-7-chloro 1,4-benzodioxan-5-(1-(2-methylbutyl)-4piperidyl)methyl carboxaxnide, hydrochloride (E46) IH NMR 250 MHz (CDCI 3 (free base) J':%OlIER'MIC\2M4I$92jIV. 19/7196 30 8: 7.70(s,1H), 7.44-7.53(m4lH), 4.24-4.37(6H-), 3.28(t,2H), 2.87(d,2H), 2.19- 2.29(m,2H), 1.75- 1.90(m,2H), 1.42- 1.7 1(m,4H), 1.15- 1.37(m,4H), 0.83(d,6H).

Example 47 8-Amino-7-chloro- 1,4-benzo dioxan- 5- (4-p iperi dylI)me thylI carboxamide hydrochloride (E47) A solution of 8-acetamido-7-chloro- 1,4-benzodioxan-5-(4-piperidyl)methyI carboxamide (D12) (1.65g) in ethanol (50mi) was treated with aqueous sodium hydroxide solution (4.5il) and the resulting mixture heated to reflux overnight. The solvent was removed in uacuo, the residue saturated with 1K2C0 3 and extracted with chloroform. The organic phase was dried (Na 2 SO4) filtered and evaporated under reduced pressure to afford 8-amaino-7-chloro-1,4-benzodioxan-5-(4piperidyl)me thylcarboxamide (0.89g). Treatment with ethereal MCI gave the title compound.

1 H NMR 250 MHz (CDCl 3 (free base) Exmpe 48 too.

8: 6.87.5(m,1H), 4.26-4.48(m,6H), 3.32(t,2H), 3.09dH) 2.59(dt,2H), .62-,3,1.8rn,3H) H, 1.1.m2-163) 1,,XOI,4RWjCq,(AIA.92,DIV' Onm -31 8-Amino-7-chloro-1,4-benzodlioxan-5- (1 -fpropyl-4-piperi dyl)me thyl carboxamide hydrochloride (E49) 1H NMR 250 MHz (CD 3 OD) (free base) 7.53(s,1H), 4.38-4.54(xn,4H), 3.57(d,2H), 3.27-3.41(m,21i), 2.83- 3.15(m,4H), 1.54-2.12(in,7H), 1.03(t,3H) 8-Amino-7-chloro- 1,4-benzodioxari-5-( L-benzyl-4-piperidyl)methyl carboxamide hydrochloride 1 H NMR 250 MHz (CDCI 3 6: 7.75(s,lH), 7.48-7.60(m,lHX, 7. 17-7.38(m,5H), 4,28-4.46(m,6H), 3.49(s,2H), 3.31(t,2H), 2.91(d,2H), -i.98(t,2H), 1.52-l.78(m,3H), 1.23- 1.42(m,2H).

M+ (El) 359 Example 51 8-Amino- 7- chloro -bu tyl- 1- me thy 1-4- p ip eri dyl) me thyl1-l,4benzodioxan- 5-carboxyla te iodide (E5 1) A solution of 8-amino-7-chloro-( 1-butyl-4-piperidyl)methyl- 1,4hydrochloride (El) (75mg) was converted to the free base then dissolved in acetone (l0mi). Iodomethane (20P4ml) was added and the mixture was heated under reflux for 3 hours. The solvent was removed in vacuo and the residue dried to give a pale yellow solid The product exists in two isomeric forms.

1 H NMR 250 MHz (DMSO) 6: 7.28(s,lH), 5.72(bs.2H), 4.28(bs,4H), 4.08(d,2H), 3.38-3.5(m,2H), 3.2- 3.37(in,4H), 3.00(s,3H), 1.20-2.05(m,9H), 0.92(t,3H).

,,omimmicamig amv isnim -32 Example 52 8-Ainino-7-iodo- 1,4-benzo di oxan- 5- (1 -bu tyl1-4-p iperi dyl)m e thylI carboxylate hydrochloride (E52) The title compound was prepared from 8-amino-7-iodo-1,4-benzodioxafl-5carboxylic acid (D1) by the method described for Example 1.

IH NMYR 250 MHz (CDCI 3 7.8 Vs, 1H), 4.53(bs,2H), 4.29-4.40(m,4H), 4.09(d,2H), 2.91-3.08(m,2H), 2.28-2.44(m,2H), 1.89-2.08(m,2H), 1.69- 1.88(m,3H), 1.23-1.60(6H), 0.93(t,3H).

Example 53 (1-Butyl-4-piperidyl)methyl-8-chloro-1,4-benzodioxan-5carboxylate (E53) :The title compound was prepared from 8-chloro-1,4-benzodioxan-5carboxylic acid 1 by the method described for Example 1.

25 mp 153-1540C (hydrocloride salt) 1 H NMR 250 MHz (CDCI 3 (free base) 6: 7.38(d,IH), 6.96(d,1H), 4.41(s,4H), 4.13(d,2H), 2.98(d,2H), 2.32(t,2H), 1.93(t,2H), 1.84-1.65(m,3H), 1.54-1.20(m,6H), 0.92(t,3H) Example 54 (1-Butyl-4-piperidyl)methyl-6,7-dibromo- carboxylate (E54) The title compound was prepared from 6,7-dibromo-1,4-benzodioxan-5carboxylic acid 1 by the method described for Example 1.

33 inp 175-177 0 C (hydrochloride salt) 1 H NMR 250MHz (CDCI 3 (free base) 7.20(s,1H), 4.30(s,4H), 4.20(d,2H), 3.02(d,2H), 2.38(t,2H), 2.00(t,2H), i.87-1.65(m,3H), 1.55-1.28(m,6H), 0.94(t,3H) Descriptions (preparation of intermediates) Description 1 (intermediate for Example 7) 8-Amino-7-iodo- 1,4-benzodioxan-5-carboxylic acid A solution of 8 -amino- 1, 4-benzodi oxan- 5-carboxylic acid 1 0.0025m) in AcOH(50m1) was treated with a solution of iodine monochloride (0.423g, 0.0026) in AcOHi(l0ml). The reaction mixture was :stirred at room temperature for two days. The solvent was removed in vacua and the residue treated with H 2 0. A red solid was obtained which was collected by filtration and washed with water. Yield=0.60g.

1H NMR (250MHz) DMSO 6: 7.69(s,1H), 5-5.5(b,1H), 4.3(s,6H) Description 2 (intermediate for Example 6) 8-Amino-6,7-dichloro-1IA-benzodioxan-5-carboxylic acid 8-Acetamido-1,4-benzodioxan-5-carboxylic acid 1 (6.14g, 0.029m) was suspended in AcOH(200m1) and a solution Of C1 2 in AcOH (52m1 of a solution of 9.6g in lO0mI) was added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the I':\OI|l\MJC2MI 8W.DIV m lnn6 -34residue was triturated with water. The precipitated solid was collected by filtration, washed with water and dried to give 6.20g product.

1H NMR (250MHz) DMSO 12.4-12.5(b,1H), 9.3(bs,1H), 4.35(s,4H), 2.07(s,3H) Description 3 (intermediate for Example 17) 1,4-Benzodioxan-5-carboxamide oxime Sodium (0.720g, 0.031 mol) was dissolved with stirrring in methanol (8ml). A solution of hydroxylamine hydrochloride (2.18g, 0.031 mol) in methanol (40 ml) was then added dropwise. The mixture was then stirred at room temperature for 1/2 hour. The reaction mixture was then filtered, and the filter pad washed with MeOH. The filtrate was then treated with 1,4-benzodioxan-5-nitrile 2 (2.52g, 0.016 mol). The reaction mixture was then stirred and heated to reflux. After 12h, the reaction mixture was 20 allowed to cool, and was evaporated under reduced pressure to give a brown oily solid. Recrystallisation of this residue from methanol gave the title compound as cream coloured crystals (2.57g) mp 146-1480C.

to* 1 H NMR (250MHz) DMSO 6: 9.42(s,1H), 6.75-6.96(m,3H), 5.62(s,2H), 4.25(s,4H) Description 4 (Z is of sub-formula Y=0) 1-Butyl-4-piperidinemethanol *6 A mixture of ethyl isonipecotate (31.4g, 0.2mole), K 2

CO

3 (54g, 0.4mole) and nBuBr (27.4g, 0.2mole) in EtOH (400ml) was stirred under reflux for 3 hours. The reaction mixture was allowed to cool, filtered through keiselguhr and the filtrate concentrated to give a pale yellow oil. This was dissolved in dry Et 2 0 (200ml) and added dropwise to a suspension of LiAIH 4 (20g, 0.26mole) in dry EtO. The reaction mixture was stirred at I sL----l I:\Ol'lilt\MMICl I I XlI/96 room temperature overnight then cooled in an ice bath. Water (20ml) was carefully added, followed by 20% aq. NaOH (20ml), followed by water The mixture was stirred at room temperature for 30 minutes then filtered through keiselguhr. The filtrate was concentrated in vacuo to give a colourless oil (25.0g).

INMR 250MHz (CDC1 3 3.48(d,2H), 2.93-2.99(bd,2H), 1.18-2.4(m,14H), 0.9(t,3H) Description 5 (Z is of sub-formula Y=O) 1-Cyclohexylmethyl-4-piperidinemethanol This compound was prepared by the method described in Description 4 from ethyl isonipecotate and cyclohexylmethylbromide.

1 H NMR 250MHz, (CDC1 3 5: 3.48(d,2H), 2.84-2.94(bd,2H), 0.78-2.4(m,21H inc. d,2H) *0 Description 6 (Z is of sub-formula

Y=NH

2 4-Aminomethyl- -cyclohexylmethylpiperidine A solution ofisonipecotamide (7g,0.055mole) in EtOH (150ml) was treated with K 2

CO

3 (13.8g, O.1mole) and cyclohexylmethylbromide (12.4g, 30 0.07mole) and the reaction mixture was heated under reflux overnight.

The mixture was allowed to cool, the solid removed by filtration through keiselguhr and the filtrate concentrated in vacuo to give a pink solid This amide was suspended in dry THF (30ml) and the suspension brought to reflux. BH 3 .Me 2 S (4.8ml) was added dropwise over 15 minutes then the mixture was heated under reflux for a further hour. Me 2 S was removed from the mixture using a reflux ratio head. Heating was continued overnight and the reaction mixture was then cooled. 5N HC1 (6ml) was added then the mixture was heated under reflux overnight.

I

PA011VIONUM'118,91DIV. lonigo 36 The solution was cooled, basified with 40%7 aq. NaOH and extracted with

CHCI

3 Drying and evaporation of solvent gave a colourless oil.

1 H NMR 250MI-z (CDCI 3 6: 2.8-2.91(bd,2H), 2,55(d,2H), 2.09(d,2H), 0.75- 1.9(m,20H) Description 7 (Z is of sub-formula Y=NH) 4-Aminom ethyl-1-butylpiperidine The title compound was prepared by the method described in Description 6 from isonipecotamide and butyl bromide.

1 H N MR 250 MHz (CDC1 3 2.88-3.0(bd,2H), 2.56(d,2H), 1.18- 1.95(m,15H), 0.92(t,3H) Description 8 (Z is epm, Y=N~H *.*.*4-Aminomethyl- 1-ethylpiperidine The title compound was prepared by the method described in Description from isonipecotamnide and ethyl iodide.

1Hi NMR 250MHz (CDCl 3 5:2.9-3.0 (bd,2H), 2.56(d,2H), 2.48(dd,2H), 1.1-1.95(m,9H), 1.05(t,3H) Description 9 (Z is pm, Y=O) N-tert-Butoxycarbonyl-4-hydroxymethylpiperidine To a stirred slurry of LiAIH 4 (14.48g) in Et9?O (200m1) was added, dropwise, a solution of ethyl isonipecotate (19.3m.1) in Et 2 O (100n Oat 0OC I':\OI'I!R M(IIIHW UW 1W1MT/ -37under a nitrogen atmosphere. Stirring was continued at room temperature overnight. The mixture was cooled and H 2 0 (14.5ml), aqueous NaOH (21.8ml) and H 2 0 (36.2ml) were added sequentially. The mixture was stirrred at room temperature for lh. The precipitate was removed by filtration through keiselguhr and the filtrate concentrated under reduced pressure to afford crude 4-hydroxymethylpiperidine (4.71g). Di-tert-butyl dicarbonate (9.83g) was added to a solution of 4hydroxymethylpiperidine (4.71g) in 50% aqueous THF. Solid K 2 C0 3 was added to the reaction mixture to maintain pH 9, and the mixture stirred overnight at room temperature. The solvent was concentrated under reduced pressure and the residue partitioned between Et20 and H 2 0.

The aqueous phase was extracted with Et 2 0 and the combined organic phase dried (Na 2

SO

4 filtered and concentrated in vacuo to afford the title compound as a pale yellow solid (6.12g).

1 H NMR 250MHz (CDC1 3 4.08-4.2(bd, 2H), 3.45-3.52(bt,2H), 2.6-2.78(m,2H), 1.58-1.9(m,4H), 1.46(s,9H), 1.03-1.22(m,2H)

V.

S. Description o eq 2-Hydroxymethylquinolizidine o was prepared by the method of N.J. Leonard et al. J. Org. Chem., 1957 22, 1445 eq 3-Hydroxymethylquinolizidine was prepared by the method of H. Lewis and C. Shoppee J. Chem. Soc., 1956, 313.

1 I':\OI'IK\M lC l 4192n,DIV. f7196 -38- Description 11 (intermediate for Example 18) a) Ethyl-1,3-benzodioxole-4-carboxylate Following the procedure outlined by J. H. Clark et al, Tetrahedron Letters No. 38, 3361, 1976, ethyl-2,3-dihydroxybenzoate (4.5g) was converted to the title compound (2.21g, 46%).

1 H NMR 250 MHz (CDC1 3 6: 7.42 1H), 6.98 1H), 6.86 1H), 6.11 2H), 4.40 2H), 1.40 (t, 3H).

b) 1,3-Benzodioxole-4-carboxylic acid A solution of ethyl-1,3-benzodioxole-4-carboxylate (D13) (Ig) in water ml) and ethanol (8 ml) was treated with 10% sodium hydroxide solution (3.1 mis) and heated at reflux for 30 minutes. After cooling, the reaction mixture was acidified with dilute hydrochloric acid, and the precipitate was filtered and washed with water to give the title compound (D13) (0.71g, 84%).

1 IH NMR 250 MHz (d 6

-DMSO)

5: 13.01 (br s, 1H), 7.29 1H), 7.13 1H), 6.90 1H), 6.13 2H).

Description 12 (intermediate for Example 47) 30 a) 8-Acetamido-1,4-benzodioxan-5-(4-pyridyl)methyl carboxamide 8-Acetamido-1,4-benzodioxan-5-carboxylic acid (2.5g) was suspended in acetonitrile (100 ml) and N,N'-carbonyl diimidazole (1.7g) was added. The reaction mixture was stirred with gentle heating, under a nitrogen atmosphere for Ih. The mixture was cooled to room temperature and the solvent concentrated in vacuo. The oil was filtered through a bed of silica using chloroform and ethanol as eluant. The oil was dissolved in I I -39dichioromethane (lO0mii) and treated with 4-(aminomethyl)pyridifle (1.17m1). The resulting mixture was heated to reflux overnight. The solution was cooled to room temperature and the solvent removed in uacuo. The residue was chromatographed on silica eluting with ethanol/chloroform to afford pure title compound as a solid (1.47g).

IH NMR 250 MHz (CDCI 3 8.58(d,2H), 8. 10(d, 1H), 7.92-8.00(in,1H), 7.82(d, 1H), 7.69(bs, 1H), 7.28(d,2H), 4.68(d,2H), 4.39-4.47(m,4H), 2.24(s,3H) b) 8-Acetamido-1,4-benzodioxan-5-(4-piperidyl)methyl carboxamide A solution of 8 -ace tamido- 1, 4- benzodi oxan- 5-(4-pyri dyl)m ethyl carboxarnide (3.0g) in acetic acid (200 ml) was hydrogenated at 50 psi over platinum (iv) oxide. After 4h the catalyst was removed by filtration through keiselguhr and the filtrate concentrated in vacuo. The residue was taken up in water, basified with K 2 C0 3 and extracted into chloroform. The organic phase was dried (Na 2

SO

4 filtered and concentrated in uacuo to afford the title compound (2.85g) 1 H NMR 250 MHz (CDCI 3 6: 8.03(d,1H), 7.70-7.80(m,2H), 7.55-7.63(rn,1HX 4.35(m,4H), 3.24(t,2H), 3.10(d,2H), 2.59(t,2H), 2.12(s,3H), 2.09(bs,lH), 1.68-1.80(m,3H), 1..1- 1.29(m,2H).

C) 8-Acetamido-7-chloro- 1,4-beazodioxan-5-(4-piperidyl) methyl 30 carboxamide A solution of 8-acetamido- 1,4-benzodioxan-5-(4piperidyl)methylcarboxamide (2.56g) in acetic acid (100 ml) was treated with a solution of chlorine (0.55g) in acetic acid (18 ml). The reaction mixture was stirred at ambient temperature overnight. The solvent was removed in uacuo to afford the title compound as a gum (D12).

IH NMR 250 MHz (CD 3

OD)

io im 01 Il i iI.. iV tnf 40 7.47(s,1H), 4.29-4.46(m,41{), 3.29-3.49(m,4H), 3.01(t,2H), 2.12- 2.21(in,3H), 1.99(s,3H), 1.43- 1.62(m,2H) Description 13 (intermediate for Example 43) 8-Acetamido-7-chloro- 1,4-benzodioxan-5- (1-pentyl-4piperidyl)methyl carboxamide To a solution of 8-acetamido-7-chloro- 1,4-benzodioxan-5-(4pipe ri dylme thyl)carb oxamide (D12) (150mg) in acetone (i1ini) was added potassiu-m carbonate (100mg) and 1-bromopentane (60 The resulting mixture was stirred overnight at ambient temperature. The solvent was removed in vacuo and the residue chromatographed on silica using chloroform and ethanol as eluant to afford pure product MD13) 1 H NMR 250 MHz (CDCI 3 8: 7.72-7.79(s,1H), 7.55-7.65(m,1H), 7.21-7.34(m, 1H), 4.32-4.50(m,4H), 3.45(t,2H), 3.03(d,2H), 2.43-2.55(t,2H), 2.15-2.29(m,3H-), 2.0 1(t,2H), 1.21- 1.82(m,11H), O.91(t,3H) Descriptions 14 to 16 (intermediates for Examples 44-4 6) Using the procedure outlined in Description 13 the following compounds were prepared: 8-Acetamcido-7-chloro-I,4-benzoioxafl-5- 1-cyclohexylethyl-4piperidyi)methyl carboxamide (D14) 1H NMR 250 NMz (CDC1 3 5: 7.70(s,IH), 7.47-7.55(m,2H), 4.30-4.47(m, 4H), 3.46(t,2H), 3.01(d,2H), 2.34-2.45(m,2H), 2.2 1(bs,3H), 1.99(t,2H), 1.57- 1.82(m,8H), 1.09- 1.49(m,8H), 0.83-1.00(m,2H) PA0111JONJIM5418.92.0tv. IBM% -41- 8-Acetamido-7-chloro-1,4-benzod-ioxan-5-( 1-isobutyl-4piperidyl)methyl carboxamide 1 H NMR 250IMIHz (CDC1 3 6: 7.73(s,1H), 7,52-7.61(m,1H), 7.22-7.32(rn,1H), 4.32-4.49(m,41{), 3.34(t,2H), 2.91(d,21H), 2.18(bs, 3H), 2.10(d,2H), 1.52-1.97(m,6H), 1.25- 1.45(m,2H), 0.89(d,6H) 8-Acetamido-7-cbloro-1,4-benzodioxan-5-( 1-(2-methylbutyl)-4piperi dyl) methyl- 1,4..benzo dioxan carboxarnide (D16) 1 H NMR 250 MHz (CDC1 3 6: 7.75(s, 1H), 7.55-7.65(m, 1H), 7.19-7.30(m, 1H), 4.33-4.5 1(zn,4H), 3.33(t,2H), 3.02(d,2H), 2.33-2.44(m,2H), 2.19(bs,3H), 2.01(t,2H), 1.37- 1.81(m,8H), 0.90(d,6H) S *20 References: l1 UK Patent 1571278 2. R.G. Fuson, Rt. Gaertner, A.D.H. Chadwick, J.Org.Chem. 1948, Ia, 489 1 n I~fionm -42- 4 RECEPTOR ANTAGONIST ACTIVITY 1) Guinea pig colon Male guinea-pigs, weighing 250-400g are used. Longitudinal musclemyenteric plexus preparations, approximately 3cm long, are obtained from the distal colon region. These are suspended under a 0.5g load in isolated tissue baths containing Krebs solution bubbled with 5% CO 2 in 02 and maintained at 37 0 C. In all experiments, the Krebs solution also contains methiothepin 10- 7 M and granisetron 10-6M to block effects at 5-HT 1 2 and 5-HT 3 receptors.

After construction of a simple concentration-response curve with using 30s contact times and a 15min dosing cycle, a concentration of is selected so as to obtain a contraction of the muscle approximately maximum(10- 9 M approx). The tissue is then alternately dosed every with this concentration of 5-HT and then with an approximately equi-effective concentration of the nicotine receptor stimulant, 20 dimethylphenylpiperazinium (DMPP). After obtaining consistent responses to both 5-HT and DMPP, increasing concentrations of a putative 5-HT 4 receptor antagonist are then added to the bathing solution. The effects of this compound are then determined as a percentage reduction of the contractions evoked by 5-HT or by DMPP. From this data, 25 values are determined, being defined as the -log concentration of antagonist which reduces the contraction by 50%. A compound which reduces the response to 5-HT but not to DMPP is believed to act as a 4 receptor antagonist.

Compounds were generally active in the range of concentrations of the order of pIC 5 0 =7 or more, with the compounds of Examples 1, 2, 3, 5, 6, 9, 11, 12, 21, 22, 25, 26, 27, 28, 30, 31, 32, 33, 35, 39, 40, 41, 42, 44, 49 and 53 having particularly good activity.

P;I\OI'fsI U( 4IUM1Ih9.DIV. 8 l1/6 43 2) Piglet Atria The compounds were tested in the piglet spontaneous beating atrium screen (Naunyn-Schmiedeberg's Arch. Pharmacol 342, 619-622). pKB logl0 KB) values for the compounds of Examples 1, 2, 5, 10, 13, 14, 52, 53 and 55 were in the range 7 to 3) Rat oesophagus Rat oesophageal tunica muscularis mucosae was set up according to Baxter et. al. Naunyn-Schmiedeberg's Arch. Pharmacol., 343, 439-446 (1991). The inner smooth muscle tube of the muscularis mucosae was isolated and mounted for isometric tension recording in oxygenated 02/5% C0 2 Tyrodes solution at 37°C. All experiments were performed in pargyline pre-treated preparations (100liM for 15 min followed by washout) and in the presence of cocaine (30M). Relaxant responses to HT were obtained after pre-contracting the oesophagus tissue with carbachol (3p.M).

SEl acted as a non-surmountable antagonist of 5-HT in rat oesophagus causing as reduction in maximum response, without significant rightward displacement of concentration effect curves.

4) 5-HT-induced motility in dog gastric pouch Compounds were tested in the in vivo method described in "Stimulation of canine motility by BRL 24924, a new gastric prokinetic agent" by Bermudez et al, J. Gastrointestinal Motility, 1990, 281-286.

Compounds showed inhibition at 10.ig kg- and El showed inhibition at lig kg-1 -e P;O:(\MICM:<i1ll.1 1)(V 1//96 44- IN VIVO TESTING FOR IBS The method is as generally described in J. Physiology, 1958, Vol. 141, pl4P-15P.

Male mice (strain: CD1; weight range 25-35g) were housed individually in perspex boxes with a mesh top and bottom for 20 min prior to dosing.

Animals were then challenged with either vehicle or 5-HTP (10mg/kg) via the subcutaneous route. Antagonists were dosed 5 min post-dose of saline or 5-HTP. The number of pellets was counted at 10 min. intervals for 1 hr. and finally after a further 15 mins (total time 75 min). The animals were sacrificed. The mean and SEM of the cumulative number of pellets was calculated.

El at 10 pg/kg had no effect on faecal pellet output when compared against saline; i.e. the compound did not constipate. 5-HTP significantly potentiated the rate of pellet output, but at this dose of 10 pg/kg whilst causing wetter pellets, did not produce diarrhoea.

El dose dependently inhibited the 5-HTP effect between 0.1-l1g/kg at 1.lg/kg-100g/kg El, the defaecation rate was returned to normal levels as seen with saline.

6 I 17 IN VIVO TESTING FOR ANXIOLYTIC ACTIVITY 1) Social Interaction Rats (male, Sprague Dawleys, Charles River, 250-300g) were housed in groups of eight in a holding room for 5 days. They were then housed singly in a room adjacent to the experimental room for 4 days prior to the experimental day. On the experimental day rats were administered vehicle El or a benzodiazepine anxiolytic, chlordiazepoxide, s.c. in pairs at 15 minute intervals beginning at 10.00 a.m. 30 mins. later they were placed with a weight matched pair-mate (encountered for the first time) in the social interaction box in a separate room. The box was made of white perspex 54 cm x 37 cm x 26 cm with a transparent perspex front side and no lid. The floor was divided up into 24 squares and the box was brightly lit (115 lux). Active social interactive behaviours (grooming, sniffing, climbing over or under, following, biting, mounting and boxing) were scored blind for the next 15 min by remote video monitoring to give total interaction scores. The number of squares crossed by each rat was also scored and summed. After the end of each test the box was carefully wiped.

El increased total interaction scores over the dose range 0.001 1.0 mg/kg S.C. Locomotion scores were not significantly altered although a trend 25 towards reduced locomotion was seen at 10.0 mg/kg S.C. This profile is consistent with anxiolysis.

2) X-Maze 30 The e was raised 50 cm above the floor and consisted of two enclosed arms 45 cm (long) x 10 cm (wide) and 10 cm (high) and two open arms 45 x 10 x 1 cm, arranged such that the two arms of each type were opposite each other. Both arm types were marked into two equal sections.

Rats were placed onto the centre of the X-maze and observed for a period of five min during which time the following parameters were recorded: 1) The number of entries on to, and the time spent on, open arms (b) closed arms, end of open arms and end of closed arms. 2) the number of sections crossed. The fear drive evoked in the open arms I_-LI II .'\Oli\MC"251I Y 1 l)V IIN -46exceeds that in the closed arms and rats typically show a clear preference for the enclosed arms. Anxiolytic drugs increase the number of entries made onto, and the time spent on, the outer half of the open arms, and also the percentage of entries made onto, and the time spent on, the whole of the open arms. These four measures of anxiety, and also the total number of sections traversed, were calculated for each animal.

At doses between 0.01 and 1.0 mg/kg El increased measures of anxiolysis (time spent on open arm, entries to end of open arm, time on open arm and entries onto open arm), without affecting locomotion over a five minute period. The most consistently affected measure was time on the open arm. This profile of action is consistent with anxiolysis and was mirrored by the positive control, chlordiazepoxide (5 mg/kg IN VIVO TESTING FOR ANTIEMETIC ACTIVITY Ferrets were dosed 10pg kg- 1 15 min before total body irradiation 20 (Bermudez et al, Br J. Cancer 1988, 58, p644) MEAN NO. VOMITS MEAN NO. RETCHES Control 14 1.6 120.3 16.1 n=8 El 6.3 1.6 81.5 11.6 Data: Mean sem Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

II q I

Claims

1. A compound of the formula: H-Y-Z wherein Z is of sub-formula: 1'C NRa' wherein is butyl or cyclohexylmethyl; and Y is 0or NH.

2. A compound according to claim 1 which is 4-aminomethyl-1-butyl piperidine

3. A compound according to claim 1 which is 4-aminomethyl-1- cyclohexylmethylpiperidine.

4. A compound according to claim 1 which is 1-butyl-4-piperidinemethanol. A compound according to claim 1 which is 1-cyclohexylmethyl-4- piperidinemethanol. DATED this 11th day of March, 1998 SmithKline Beecham p.l.c. By DAVIES COLLISON CAVE Patent Attorneys for the Applicants. ABSTRACT This invention relates to compounds which are intermediates useful in the preparation of

5-HT 4 receptor antagonists. These compounds have the formula: H-Y-Z wherein Z is of sub-formula: C NRa I wherein is C 3 1 2 alkyl; and Y is 0 or NHT. 0* 0 0 0 00 0000 0 000f 0 0000 00 0 0 00.0 *0 00 0 0000 0000 0 0* 00 0 M